Environmental Polyethylene Terephthalate Micro‐ and Nanoplastics Promote Clear Cell Renal Cell Carcinoma Progression Through Mitochondrial ROS‐Associated AKT/GSK3β/β‐Catenin Signaling

Environmental polyethylene terephthalate micro- and nanoplastics (PET-MNPs) are biologically accessible contaminants, but their effects on clear cell renal cell carcinoma (ccRCC) progression remain unclear. Using 786-O and CAKI-1 cells and subcutaneous and orthotopic xenograft models, we found that PET-MNP exposure enhanced malignant phenotypes and tumor growth, accompanied by increased intracellular and mitochondrial ROS. Mitochondrial superoxide accumulation was associated with membrane depolarization, reduced ATP levels, ultrastructural abnormalities, and decreased SOD2 expression and Mn-SOD activity. Mechanistically, PET-MNP exposure increased AKT and inhibitory GSK3β Ser9 phosphorylation, reduced degradation-associated phosphorylation and ubiquitination of β-catenin, and enhanced β-catenin stability, nuclear accumulation, and transcriptional activity. Time-course analysis indicated that AKT activation preceded prominent GSK3β and β-catenin changes. MitoTEMPO, pharmacological AKT or β-catenin inhibition, AKT knockdown, β-catenin-S33Y rescue, and GSK3β-S9A experiments further supported the functional involvement of mitochondrial ROS-associated AKT/GSK3β/β-catenin regulation. ChIP-qPCR and RT-qPCR showed increased β-catenin recruitment to MYC and CCND1 regulatory regions and enhanced transcription. These findings support a role for mitochondrial ROS-associated AKT/GSK3β/β-catenin regulation in PET-MNP-promoted ccRCC progression.